Primary target

New therapies show promise as add-ons to statins which aim at reducing LDL Cholesterol

Globally, cardiovascular disease is the leading cause of death. According to the World Health Organisation, cardiovascular disease represents 30 per cent of all global deaths and, if current trends remain, an estimated 20 million people will die annually from it by 2015 (mainly from coronary heart disease and stroke). Over the years, the Framingham Heart study has identified several risk factors associated with the development of cardiovascular disease. One of these is high cholesterol, or hypercholesterolaemia.

Hypercholesterolaemia is characterised by elevated cholesterol in the blood due to abnormalities in the levels of lipoproteins. Elevated levels of the lipoprotein fractions, low density lipoprotein (LDL), intermediate density lipoprotein and very low density lipoprotein, and low levels of high density lipoprotein (HDL) have been shown to be positively correlated with the development of atherosclerosis, which is the underlying cause of cardiovascular diseases.

The National Cholesterol Education Programme (NCEP) Adult Treatment Panel (ATP) III guidelines identify LDL cholesterol as the primary target for the treatment of hypercholesterolaemia. In general, the ATP III guidelines now recommend that LDL cholesterol levels be brought below 100 mg/dL in high-risk and moderate-risk patients. Recently, it was suggested that the target should be as low as 70 mg/dL.

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Statins, or HMG-CoA reductase inhibitors, are the most potent LDL cholesterol-lowering agents available. Despite the success of statins, it is estimated that 5-10 per cent of patients cannot be treated with them, owing to side effects or lack of response. There are several new therapies under investigation that may be attractive as add-on therapy to statins, or useful as second-line therapy. Eprotirome (KB 2115; Karo Bio) is a first-in-class thyroid hormone receptor β-agonist that is being developed for the treatment of dyslipidaemia. It has been known for a long time that thyroid hormone reduces cholesterol, but it is associated with undesirable effects on the heart and bones. Eprotirome acts specifically on thyroid hormone receptors in the liver and lowers cholesterol and triglycerides. Results from a recent phase II trial presented at the American College of Cardiology meeting in March 2009 showed that eprotirome (25-100 μg/day) significantly dose-dependently reduced LDL cholesterol by 21 per cent to 32 per cent after 12 weeks in patients with hypercholesterolaemia already receiving statins. Additionally, no adverse changes in heart rate, cardiac rhythm, hypothalamic-pituitary-thyroid axis or markers of bone and skeletal muscle were observed. Karo Bio intends to license eprotirome at a later stage of development.

AVE 5530 (sanofi-aventis), a cholesterol absorption inhibitor, is currently being developed for the treatment of hypercholesterolaemia. AVE 5530 has the potential to be used as monotherapy or in combination with statins. Results from a phase IIb study in 196 patients with mild-to-moderate hypercholesterolaemia showed a significant reduction in LDL cholesterol. Sanofi-aventis has initiated patient enrolment in a phase III trial assessing the efficacy and tolerability of AVE 5530 (25 and 50mg/day) in addition to ongoing treatment with high doses of statins in patients with severe primary hypercholesterolaemia. The estimated completion date for this trial is April 2010. Regulatory filing is anticipated in 2010 for both monotherapy and a fixed dose combination with a statin.

Mipomersen sodium (ISIS 301012; Isis Pharmaceuticals, Genzyme) is a first-in-class oligonucleotide antisense inhibitor directed against apolipoprotein B 100 mRNA. Mipomersen sodium is initially being developed for the treatment of homozygous familial hypercholesterolaemia. It received orphan drug status for this indication in the US in 2006. Phase II trials have indicated that treatment with mipomersen sodium results in significant reductions in LDL cholesterol. Genzyme is currently enrolling patients into its phase III RADICHOL II trial, designed to evaluate efficacy and safety of dosing with mipomersen for 26 weeks in subjects with heterozygous familial hypercholesterolaemia and coronary artery disease on lipid-lowering therapy. The trial is scheduled for completion in May 2010.

AEGR 733 (Aegerion Pharmaceuticals), a microsomal triglyceride transfer protein (MTP) inhibitor, is currently being developed for the treatment of primary and familial hypercholesterolaemia. Microsomal triglyceride transfer protein inhibitors have a dual mechanism to reduce both LDL cholesterol and triglyceride levels. Three phase II trials designed to evaluate the efficacy, safety and tolerability of low doses of AEGR 733 alone and in combination with other lipid-lowering agents, atorvastatin, ezetimibe or fenofibrate in patients with dyslipidaemia (n = 460) have demonstrated significant lowering of LDL cholesterol with a promising hepatic safety profile. Currently, there is a phase III trial underway in the US, Canada and South Africa in approximately 25 patients with familial hypercholesterolaemia on current lipid-lowering therapy. Preliminary results show LDL cholesterol reductions of greater than 50 per cent (beyond the existing reductions patients experienced on background therapy) in the majority of patients that have reached high dosages in the study.

Choline fenofibrate (TriLipixTM; Abbott Laboratories, Solvay), a peroxisome proliferator-activated receptor alpha agonist, was approved on 15 December 2008 for the treatment of lipid disorders such as hypercholesterolaemia and hyperlipidaemia. Choline fenofibrate is also being developed as a fixed combination therapy with AstraZeneca's rosuvastatin (Crestor) for the treatment of patients with mixed lipid disorders. The combination is being developed to reduce LDL cholesterol and triglycerides, while increasing HDL cholesterol. A phase III trial was initiated in the US in April 2007, which evaluated choline fenofibrate and rosuvastatin combination therapy in patients with type IIa and type IIb dyslipidaemia. Results presented at the American College of Cardiology meeting in March 2009 showed that the combination resulted in significant reductions in triglycerides (by 40.3 per cent) and LDL cholesterol (28.7 per cent). NDA filing is anticipated in Q3 2009.

Reducing LDL cholesterol is still the most important target for reducing cardiovascular risk in patients with hypercholesterolaemia. While statins are the most potent drugs available for the reduction of LDL cholesterol and play a fundamental role in the management of this disease, these new therapies will have a place in patients with specific lipid disorders and in those who are unresponsive or intolerant to statins. After the findings of the JUPITER (Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin) trial, the most successful future therapies may be those with the ability to reduce dramatically both LDL cholesterol and C-reactive protein.

The AuthorPipeline was written by Celeste Burness of Adis International (Wolters Kluwer Health), using data derived from Adis R&D Insight and Clinical Trial Insight. For further information on Adis services, please contact Camille Scot-Smith on 020 7981 0733.To comment on this article email pm@pmlive.com